Multiple sclerosis (MS) remains the leading cause of neurological nontraumatic disability for young adults in North America. This Program Project competing renewal application is a direct extension of our research during the past period of support, and is based on interlinked hypotheses regarding the inflammatory destructive and neurodegenerative processes in MS patients, which begins from disease onset and culminates in progressive neurologic disability due to accumulated, irreversible tissue injury. The program consists of four related projects and one multifunctional core. Project 1: Chemokines and chemokine receptors in multiple sclerosis. The competing renewal will define in detail how individual receptors govern infiltration of monocytes in acute lesions and address for the first time differential trafficking by CD4+ and CD8+ T cells. We intend further to determine how chemokine receptors govern movement of T cells and APCs in acute and chronic MS lesions. We will use a BBB model to address the differences we observe in chemokine receptor expression by cells in blood, CSF and brain parenchyma. Proiect 2: Axonal pathology in multiple sclerosis proposes that axonal pathology is a primary contributor to neurological deficits in MS patients and should be considered as a therapeutic target. The competing renewal focuses on molecular mechanisms of neurodegeneration in MS brain and spinal cord, based upon the hypothesis that degeneration of chronically-demyelinated axons results from reduced axonal energy metabolism, which, in turn, alters the ionic milieu of the axoplasm, culminating in increased intraxonal Ca++ and axonal degeneration. Project 3: Monitoring brain atrophy during the course of multiple sclerosis has established that brain atrophy is a practical, sensitive and relevant surrogate marker of the underlying disease process. However, determinants of variance in rate of atrophy remain undefined. This issue will be addressed by use of advanced MRI techniques to analyze changes in individual lesions and examination of diffuse and regional tissue damage. Proiect 4: Biomarkers of the therapeutic response in MS will use innovative strategies for determining IFN responder status and cDNA macroarrays to monitor the genetic program of response to IFN, to address molecular markers of response to IFN in MS patients. Core: Tissue acquisition, biostatistics, MRI imaging, administration will provide data analysis/management and administrative support for projects, establish, maintain and distribute for projects a unique resource of MS autopsy tissue, and coordinate imaging protocols. This research program will continue to impact our understanding of MS and lead to novel treatments.